In its broadest sense, dermatitis is inflammation of the skin. It is a common and disfiguring skin condition which requires quick and efficient treatment. Dermatitis symptoms vary, however, with the different forms of the condition. Symptoms vary from skin rashes to bumpy rashes through to flaky skin and blisters. Although different types of dermatitis have varying symptoms, there are certain signs that are common for all of them, including redness of the skin, swelling, itching, skin lesions and sometimes oozing and scarring.
Also, the area of the skin on which the symptoms appear tends to be different with every type of dermatitis. Types of dermatitis are classified according to the cause of the condition. Contact dermatitis is caused by an allergen or an irritating substance. Irritant contact dermatitis accounts for 80% of all cases of contact dermatitis.
Atopic dermatitis is very common worldwide and increasing in prevalence. Atopic dermatitis is a type of eczema and is an inflammatory, chronically relapsing, non-contagious and itchy skin disorder.
Other less common forms of dermatitis include dermatitis herpetiformis. It is characterized by intensely itchy, chronic papulovesicular eruptions, usually distributed symmetrically on extensor surfaces such as the back of neck, scalp, elbows, knees, back, hairline, groin or face.
Seborrheic dermatitis is a dermatitis that occurs in the vicinity of sebaceous glands and is caused by sebum over production. The condition tends to give a scaly, flaky skin condition.
Stasis dermatitis is an inflammation on the lower legs which is caused by build up of blood and fluid and it is more likely to occur in people with varicose veins.
Infective dermatitis is dermatitis secondary to a skin infection. A summary of dermatitis can be found in Blauvelt et al in Chapter 11 of J Allergy Immunol February 2003. Here the author, in particular, discusses allergic and immunological diseases of the skin, such as allergic contact dermatitis.
The present inventors seek new treatments for all types of dermatitis with particular emphasis on atopic dermatitis and contact dermatitis. The use of the compounds of the invention in allergic contact dermatitis is particularly considered.
There are numerous therapies for dermatitis on the market. Treatment of dermatitis is made according to the particular cause of the disease. Creams that contain corticosteroids are frequently used and simply avoiding the allergens and irritants are part of most treatment plans. For some types of dermatitis, non-steroidal medications may help relieve signs and symptoms. For all types of dermatitis, occasional use of over-the-counter antihistamines can reduce itching. Calamine lotion type products might be applied to the skin or a barrier cream such as zinc oxide or a suntan lotion might be used. For other conditions, a doctor might just advise letting the body's natural mechanisms sort the problem.
The present inventors have realised that the compounds discussed herein, compounds based upon long chain unsaturated fatty acid molecules, have potential in the treatment of dermatitis, in particular, atopic or contact dermatitis.
The compounds proposed for use in this invention have been disclosed before, for example, in EP-A-1469859 but only in the treatment of psoriasis which is a skin condition but is not a form of dermatitis. Psoriasis has very different biochemistry/immunology. The compounds have also been suggested, in WO2010/139482, for the treatment of glomerulonephritis or for the treatment of rheumatoid arthritis in WO2012/028688. The present inventors have realised that these compounds and others have utility also in the treatment of dermatitis.
It is generally accepted that the compounds of the present invention induce anti-inflammatory effects through modulation of TNFα initiated pro-inflammatory intracellular signalling cascades leading to transcription factor NF-κB activation in activated keratinocytes, which explains the compounds anti-inflammatory potential in diseases such as psoriasis and rheumatoid arthritis.
Oxazolone induced contact hypersensitivity in mice is a widely used model for delayed-type hypersensitivity (type IV hypersensitivity) with T-cell driven inflammation following challenge in previously sensitized skin. Examples of diseases where delayed-type hypersensitivity plays a significant role for disease development and clinical signs are Dermatitis including Contact Dermatitis and Atopic Dermatitis.
Psoriasis is an autoimmune induced, chronic disease of skin, characterized by T-cell accumulation, inflammation and hyperproliferation of keratinocytes in epidermis, as opposed to dermatitis being a delayed-type IV hypersensitivity disorder, the latter primarily driven by MHC class II restricted CD4+ T cells.
The present inventors have surprisingly found that after oxazolone challenge, the compound of the invention surprisingly had marked anti-inflammatory effects shown by the ability to reduce oxazolone induced ear swelling. The effect was observed at very low concentrations of active compound (down to 0.01% active compound in the topical formulation) and shows that the compounds of the present invention surprisingly have anti-inflammatory effects through a previously unknown pathway that significantly inhibit delayed-type hypersensitivity mediated inflammatory pathways.
Consequently, the compounds of the present invention surprisingly have clinical beneficial effects in dermatitis including Contact Dermatitis and Atopic Dermatitis.
The present inventors have therefore shown that compounds claimed herein are able to suppress oxazolone induced delayed-type-hypersensitivity (DTH) responses in mice.